PROJECT SUMMARY Only 59% (29-73%) of Alaska Native people have been adequately screened for colorectal cancer (CRC), which could save lives, despite having the highest reported incidence of CRC in the world. A new at-home multi-target stool DNA screening test (MT-sDNA; Cologuard) with high sensitivity for pre-cancerous polyps and CRC is now available. MT-sDNA has not been tested for feasibility or acceptability within the Alaska tribal health care delivery system, and it is unknown whether use of this new test will increase Alaska Native CRC screening rates. Our long-term goal is to improve screening and reduce CRC-attributable mortality. The objective of this application is to test the effectiveness of MT-sDNA for increasing CRC screening in Alaska Native communities using a mixed methods, community-based participatory research (CBPR) approach. The study will be conducted in collaboration with regional Tribal health organizations who are responsible for providing health care to geographically remote Alaska Native communities. This research has been requested by Tribal organizations. Although the proposed implementation strategy is evidence-informed and promising, it is novel in that MT-sDNA has not been evaluated in the tribal health setting or among rural/remote populations. Using the Social Ecological Model, our research will be multi-level, examining influence on patients, providers, and tribal health organizations (THOs). This research study will pursue two specific aims: (1) Identify patient-, provider-, and system-level factors associated with CRC screening preferences, uptake, and follow-up; and (2) test the effectiveness of graded intensity MT-sDNA intervention in the Alaska Native community setting. For the first aim, focus groups with Alaska Native people who are non- or inadequately adherent to CRC screening guidelines, and surveys and interviews with healthcare providers will be used to identify individual, interpersonal (provider), and health system factors for future intervention. For the second aim, a three-arm cluster randomized controlled trial (high intensity with patient navigation, medium intensity with mailed reminders, usual care) will provide evidence on the usefulness of MT-sDNA in remote tribal communities as well as the first data on MT-sDNA diagnostic follow up adherence rates in the Alaska Native population. This aim will also provide evidence on the usability of MT-sDNA in the Alaska setting by evaluating MT-sDNA sample quality and neoplastic yield, which will inform plans to scale-up the intervention model. This project is innovative because an effective strategy for achieving higher screening rates than current practice could lead to increased prevention or early detection of CRC cases among Alaska Native people. The proposed research is significant because it will address a health disparity of community concern. This research has the potential to sustainably improve public health by increasing CRC screening rates among a rural/remote tribal population as well as provide a model for other integrated health systems that provide care to high-risk or underserved populations in the U.S. and worldwide. Project Summary/Abstract